CD46 is a human-specific membrane protein with numerous signaling and receptor properties. Despite the multifunctional nature of this protein, little is known about the molecular mechanisms underlying its biological phenotypes. Several viruses and bacteria target CD46, using it as a receptor or downregulating it in infected cells. Pathogenic Neisseria (N. gonorrhoeae and N. meningitidis) interact with epithelial cell CD46 at multiple levels. Infection via the Type IV pilus triggers its phosphorylation, alters its trafficking, and causes its secretion. We present evidence that Neisseria infection also stimulates its proteolytic processing by the endogenous protease complex Presenilin/3- Secretase (PS/3-S), an event that is linked to bacterial invasion. We present a model for PS/3-S processing of CD46, and propose to test predictions arising from this model. Our overall goal is to provide a strong molecular framework for understanding the numerous regulatory activities of CD46, including its role in infection. PUBLIC HEALTH RELEVANCE: CD46 is a human specific protein that regulates many functions of the immune system. There are four abundant isoforms of CD46. The relative levels of these isoforms helps to determine biological outcomes controlled by CD46. CD46 is also the target for many viruses and bacteria - human herpes virus 6, adenovirus, Group A Streptococci, Neisseria meningitidis and Neisseria gonorrhoeae. Our goal is to understand how Neisseria regulates the activity of CD46 through the Presenilin/3-Secretase protease. Knowledge gained from these studies will hopefully guide the development of strategies to control microbial infections and intervene in non-infectious diseases that involve CD46.